Evidence Report/Technology Assessment

Number 22

Prepared for:
Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services
2101 East Jefferson Street
Rockville, MD 20852
http://www.ahrq.gov

Contract No. 290-97-0001

Prepared by:
Southern California Evidence-based Practice Center/RAND
George C. Velmahos, MD, PhD
Principal Investigator
Jack Kern, PhD
Linda Chan, PhD
Danila Oder
James A. Murray, MD
Paul Shekelle, MD
Investigators

AHRQ Publication No. 01-E004

November 2000

ISBN 1-58763-008-7
ISSN 1530-4396

On December 6, 1999, under Public Law 106-129, the Agency for Health Care Policy and Research (AHCPR) was reauthorized and renamed the Agency for Healthcare Research and Quality (AHRQ). The law authorizes AHRQ to continue its research on the cost, quality, and outcomes of health care, and expands its role to improve patient safety and address medical errors. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

ISBN 1-58763-008-7

ISSN 1530-4396

The Agency for Healthcare Research and Quality (AHRQ), formerly the Agency for Health Care Policy and Research, through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments.

To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release.

AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality.

We welcome written comments on this evidence report. They may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852.

John M. Eisenberg, M.D.	Douglas B. Kamerow, M.D.
Director	Director, Center for Practice and Technology Assessment
Agency for Healthcare Research and Quality	Agency for Healthcare Research and Quality

The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, test, treatment, or other clinical service.

This project's goals are to evaluate the existing literature, summarize the evidence, and perform meta-analysis and cost-effectiveness analysis on data relevant to prevention of venous thromboembolism after injury. Venous thromboembolism occurs frequently after trauma and causes significant mortality and long-term disability. At the same time, methods to prevent and diagnose it are highly controversial and physicians' practices vary widely. With this evidence report, we intend to examine these controversial areas by analyzing the existing scientific literature. An equally important objective is to identify areas in which evidence is lacking in order to direct future research.

Three databases were searched: MEDLINE (1966--99), EMBASE (1980--99), and the Cochrane Controlled Trials Register (1980--99). The following medical subject headings were used: Thrombophlebitis, Thrombosis, Thromboembolism, Pulmonary embolism, Wounds and injuries; the subheadings: pc (prevention and control), in (injuries); and the text words: prevent$, thromboprophyla$, prophylac$, trauma$, posttrauma$, post-trauma$.

Studies were selected if they specifically reported on methods of venous thromboembolism prevention and screening in trauma patients. Studies including only nontrauma patients were rejected. A panel of technical experts assisted in identifying four key questions:

Studies were selected if they addressed any of these four questions.

Screening of 4,093 relevant titles by two independent reviewers resulted in acceptance of 2,437 of them for abstract review; 227 of these were accepted for further review. Finally, 73 studies were analyzed. Meta-analysis and supplemental analyses were performed on the available data.

The reported incidence of deep venous thrombosis in trauma patients in the selected studies is 12 percent and varies from 3 percent to 23 percent according to study design, type of trauma population, and method of deep venous thrombosis prophylaxis and diagnosis. The reported incidence of pulmonary embolism in these studies is 1.5 percent and varies from 0.1 percent to 15 percent. Few randomized controlled trials provided data that could be combined for meta-analysis. From the limited data available, there is no evidence that mechanical prophylaxis or low-dose heparin is superior to no prophylaxis or to each other for prevention of deep venous thrombosis. The role of low-molecular-weight heparin in trauma patients is unclear because the few relevant studies are heterogeneous. Spinal fractures and spinal-cord injuries increase the risk of venous thromboembolism. No relevant data are available for drawing conclusions about the best method of screening for venous thromboembolism. Although vena cava filter placement in selected trauma patients may decrease the incidence of pulmonary embolism and fatal pulmonary embolism, the designs of the studies reporting these results do not allow definitive conclusions to be drawn.

The evidence on prevention of venous thromboembolism after injury is scanty. Many practices are based on extrapolations from data on nontrauma patients. The risk of venous thromboembolism increases in the presence of spinal trauma with or without injury to the spinal cord. Currently, the most frequently used methods of venous thromboembolism prophylaxis do not offer a proven benefit over no prophylaxis. There is a pressing need for well-designed studies that will identify the best method of prevention of venous thromboembolism in trauma patients.

This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders.

Suggested Citation:
Velmahos GC, Kern J, Chan L, et al. Prevention of Venous Thromboembolism After Injury. Evidence Report/ Technology Assessment No. 22. (Prepared by Southern California Evidence-based Practice Center/RAND under Contract No. 290-97-0001.) AHRQ Publication No. 01-E004. Rockville, MD: Agency for Healthcare Research and Quality. November 2000.

Venous thromboembolism (VT) is major national health problem, claiming 50,000 lives and resulting in 300,000 to 600,000 hospitalizations annually in the United States. VT presents in two forms: deep venous thrombosis (DVT) and pulmonary embolism (PE). Injured patients are at high risk for VT because of changes in coagulation and thrombolysis mechanisms that are induced by trauma.

Methods of prevention of VT include, among others, sequential compression devices (SCDs), low-dose heparin (LDH), low-molecular-weight heparin (LMWH), vena cava filters (VCFs), and combinations of these. All these methods are associated with contraindications and morbidity. Therefore, selecting the appropriate method for the appropriate trauma patient is important. The difficulty of selecting the appropriate prophylaxis is in part a result of the inconclusiveness of the relevant trauma literature. This allows wide variability among physicians' practices and prevents consistency in quality of care.

With this report, we evaluate and meta-analyze the existing data in the literature to produce scientific answers in controversial areas related to this topic. We also identify research gaps in areas in which the scientific evidence is absent or minimal, and we hope to assist interested organizations in producing relevant guidelines and in directing future research.

A panel of 17 technical experts, consisting of national authorities in the field and representing the academic, private, and managed care sectors, was formed to assist in the design and execution of the project. Important questions on the topic were distributed to the experts, who ranked them in order of importance. After two conference calls, four refined key questions were developed:

The panel decided to use data restricted to trauma patients only and to avoid extrapolations of conclusions from nontrauma patients to the trauma population. Defining "the trauma patient" was difficult. The panel decided to exclude elderly patients with injuries following low-energy trauma (such as hip fractures after ground-level falls) from consideration. We subsequently developed causal pathways for each key question. We felt it was important to report on the rates of DVT and PE from combined literature data because these rates varied widely among studies.

We summarized the existing evidence on all trauma patients included in the available literature as well as that on individual trauma patient groups (orthopedic trauma, neurosurgical trauma, minor trauma) when data were available. We evaluated the quality of studies included in our analysis using previously published methods of determining quality scores. We entered all data in a computerized database specifically designed for this project.

We searched three literature databases: MEDLINE (1966--January 31, 1999), EMBASE (1980--January 31, 1999), and the Cochrane Controlled Trials Register (1980--January 1999). After a broad initial search, we performed multiple literature searches tailored to each question. Finally, we identified a total of 4,093 titles, which were screened according to specific inclusion and exclusion criteria by two independent medical reviewers. A third reviewer assisted in case of disagreements. After screening, 2,437 titles were accepted for abstract review. All three reviewers screened all abstracts against specific criteria; 227 of these were accepted for complete review. Of 225 articles retrieved, 73 were accepted for meta-analysis. We designed forms to extract relevant data on study design and quality, methods used, risk factors, and outcomes. Two reviewers extracted data, which were re-examined by a third reviewer. Discrepancies were resolved in meetings among all three reviewers. A random-effects model was used for all pooled results.

We first evaluated the reported incidence of DVT and PE in trauma patients. We extracted these rates from all studies as well as from studies grouped together by study design randomized, nonrandomized comparative cohorts, single cohort), method of VT diagnosis (routine screening or based on clinical suspicion), use of VT prophylaxis (yes or no), and type of trauma patients (all trauma, orthopedic trauma, neurosurgical trauma, minor trauma).

We addressed the question of the best method of VT prophylaxis in three ways:

• We examined the incidence of DVT and PE after combining groups of patients from different randomized trials who received LDH or LMWH or mechanical prophylaxis (MP) or no prophylaxis.
• We performed a meta-analysis of randomized controlled trials (RCTs) evaluating the same methods of prophylaxis.
• We performed a meta-analysis of RCTs and non-RCTs evaluating the same methods of prophylaxis.

This last meta-analysis, although methodologically weak, was performed, because the number of RCTs available for the first meta-analysis was limited.

We addressed the question of risk factors for developing VT by performing meta-analysis on studies (RCT and non-RCT) that used risk factors as either dichotomous variables (e.g., age greater or lower than 55) or continuous variables (e.g., age, without specifying a particular age cutoff point). We evaluated six dichotomous risk factors (gender, head injury, long-bone fracture, pelvic fracture, spinal fracture, and spinal-cord injury) and three continuous risk factors (age, Injury Severity Score [ISS], and units of blood transfused).

We were unable to address the question about methods of screening for VT using the current literature data. Only three studies addressed this issue in trauma patients, and each compared different methods of screening. The data could not be combined for analysis.

We addressed the question about VCFs by combining studies that included patients treated with VCF and patients without VCF and estimating the rates of PE in the two groups. None of these studies was an RCT. Other outcome parameters relevant to VCF placement, such as related complications, long-term outcome, or appropriate population to be treated with this modality, could not be extracted from the limited data available.

We also performed supplemental analyses on the two most frequent complications related to prophylactic heparin administration-bleeding and thrombocytopenia-as well as on the incidence of fatal PE and the length of hospital stay in patients who develop VT. Finally, we developed a cost-effectiveness model.

• The reported incidence of DVT and PE varies widely among different studies depending on study design, type of trauma patients included, and methods of screening and prophylaxis. The pooled rates of DVT and PE across all studies are 11.8 percent (95 percent confidence interval [CI]: 0.104, 0.131) and 1.5 percent (95 percent CI: 0.011, 0.018), respectively.
• Only a few RCTs address methods of VT prophylaxis in trauma patients. Most of these studies use different methods. Combining the limited data from studies using the same methods produces small sample sizes.
• LDH is not statistically superior to no prophylaxis in preventing VT after injury (odds ratio [OR]: 0.965, 95 percent CI: 0.353, 2.636). This conclusion is based on meta-analysis of four RCTs with a total of 219 patients.
• MP is not statistically superior to no prophylaxis in preventing VT after injury (OR: 0.769, 95 percent CI: 0.265, 2.236). This conclusion is based on meta-analysis of three RCTs with a total of 234 patients.
• The addition of non-RCTs to the meta-analyses of studies examining DVT rates in trauma patients receiving LDH vs. no prophylaxis or MP vs. no prophylaxis does not change the above conclusions.
• Comparison of LMWH vs. LDH shows no statistically significant difference between the two methods in preventing PE (OR: 3.010, 95 percent CI: 0.585, 15.485). This conclusion is based on meta-analysis of three studies reporting on the incidence of PE (two RCTs and one non-RCT, total number of patients: 355). Although the difference in PE rates is not statistically significant, the limits of the 95 percent confidence interval for this result are very wide.
• Three RCTs (one of them with the highest possible quality score) showed separately statistical superiority of LMWH against LDH or SCD in preventing DVT. The reported DVT rates vary widely among these studies (38 percent, 7 percent, and 2 percent). Because the method of prophylaxis used to compare against LMWH was not the same, meta-analysis was not done.
• Comparison of LDH vs. MP after meta-analysis of seven studies (four RCTs and three non-RCTs, total number of patients: 620) shows no statistically significant difference between the two methods in preventing DVT (OR: 1.161, 95 percent CI: 0.495, 2.723).
• Spinal fractures and spinal-cord injury are risk factors for DVT. Other frequently reported risk factors, such as head injury, pelvic fractures, or long-bone fractures, were not shown in the meta-analysis to increase the risk for DVT. It is possible that the studies reporting on these factors included severely injured patients who were already at high risk regardless of the presence of the individual risk factor.
• Trauma patients who develop DVT are older and have more severe injuries than patients who do not develop DVT. However, a specific age or ISS threshold could not be extracted from the available data.
• The reported incidence of PE in patients who undergo VCF placement is 0.2 percent, which is lower than the incidence observed in concurrently managed patients without VCF (1.5 percent) and historical controls without VCF (5.8 percent). The observational design of these studies does not allow firm conclusions to be drawn.
• LDH or LMWH administration for VT prophylaxis produces a low and similar incidence of adverse events: on average, 3 percent for bleeding and 1 percent for thrombocytopenia. These low rates may occur because patients at high risk for bleeding were not given heparin.
• Fatal PE has been reported in one-third of trauma patients who develop PE, based on data from 16 studies that reported on both rates (PE and fatal PE).
• The length of hospital stay in patients who develop DVT is significantly longer (by 15 days) relative to patients without DVT. Although a cause-effect relationship between DVT and length of hospital stay cannot be established, DVT is associated with increased costs and use of health care resources.
• There are significant gaps in the literature regarding the prevention of VT after trauma.

Future research should be directed to two areas: identifying the appropriate groups of trauma patients in need of VT prophylaxis and evaluating different methods of prophylaxis with regard to their safety and efficacy in trauma patients. Although evaluating different methods of screening for DVT would be useful, we do not feel that this should be a priority for future research. Duplex ultrasonography is the most convenient, noninvasive, and inexpensive method of screening severely injured patients. Even if other methods of screening prove to be more sensitive, associated technical and logistical difficulties make them impractical.

To address the two above areas, we propose a large multicenter trial. This trial should have a randomized controlled design, compare the most commonly used methods of prophylaxis (LDH, LMWH, SCD), identify DVT by routine screening, and evaluate multiple risk factors. Based on the findings of this evidence report, a no-prophylaxis group should be included.

Equally important future research should be directed towards evaluating the role of VCF in trauma patients. This question could be incorporated in the multicenter trial proposed above or become the sole objective of a separate randomized trial. Both designs should have a predetermined protocol for diagnosing PE, an aggressive autopsy policy to identify the cause-effect relationship of PE to death, and careful, long-term followup to detect VCF-related complications.